Beta-lactamase inhibitors

ABSTRACT

Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 62/010,974, filed Jun. 11, 2014, which is hereby incorporated byreference in its entirety.

FIELD OF INVENTION

The present invention relates to boron-containing compounds,compositions, preparations and their use as inhibitors of beta-lactamaseenzymes and as antibacterial agents.

BACKGROUND OF THE INVENTION

Antibiotics are the most effective drugs for curing bacteria-infectiousdiseases clinically. They have a wide market due to their advantages ofgood antibacterial effect with limited side effects. Among them, thebeta-lactam class of antibiotics (for example, penicillins,cephalosporins, and carbapenems) are widely used because they have astrong bactericidal effect and low toxicity.

To counter the efficacy of the various beta-lactams, bacteria haveevolved to produce variants of beta-lactam deactivating enzymes calledbeta-lactamases, and in the ability to share this tool inter- andintra-species. These beta-lactamases are categorized as “serine” or“metallo” based, respectively, on presence of a key serine or zinc inthe enzyme active site. The rapid spread of this mechanism of bacterialresistance can severely limit beta-lactam treatment options in thehospital and in the community. Currently available beta-lactamaseinhibitors (for example, clavulanic acid and tazobactam) are poorlyactive against the diversity of beta-lactamase enzymes (both serine- andmetallo-based) now emerging clinically. There is an urgent need for newbeta-lactamase inhibitors with broadened enzyme spectrum.

SUMMARY OF THE INVENTION

Described herein are compounds that modulate the activity ofbeta-lactamases. In some embodiments, the compounds described hereininhibit beta-lactamases. In certain embodiments, the compounds describedherein are useful in the treatment of bacterial infections.

In one aspect, provided herein are compounds of Formula I orpharmaceutically acceptable salts, tautomers, or N-oxides thereof:

wherein:

-   -   L is a bond, —C(R¹R²)—, —C(═O)—, or ═C(R¹)—;    -   M is a bond, —O—, —S—, —S(O)—, —S(O)₂—, or —N(R⁴)—;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, 3, or 4;    -   Z is —C(═O)—, —C(═S), or —S(O)₂—;    -   A is CycA, ArA or HetA, wherein        -   CycA is an optionally substituted 3-10 membered non-aromatic            carbocycle, wherein an optional olefin functionality of the            non-aromatic carbocycle is not directly attached to an            oxygen, sulfur, or nitrogen substituent;        -   ArA is an aromatic or heteroaromatic ring system optionally            substituted with one or more substituents selected from the            group consisting of fluoro, chloro, bromo, —CN, optionally            substituted C₁-C₆ alkyl, optionally substituted C₃-C₆            cycloalkyl, optionally substituted heterocycle, optionally            substituted aryl, optionally substituted heteroaryl, —OH,            —OR¹⁰, and —SR¹⁰;        -   HetA is an optionally substituted non-aromatic heterocyclic            ring system;    -   each R¹ and R² is independently selected from the group        consisting of hydrogen, fluoro, chloro, bromo, optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₆        cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, and —NR⁴R⁵,        -   or R¹ and R² taken together form an oxo, oxime, or an            optionally substituted carbocycle        -   or optionally substituted heterocycle with the carbon to            which they are attached;    -   each R^(d), R⁴, and R⁵ is independently selected from the group        consisting of hydrogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted aminoalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkylalkyl,        optionally substituted heterocyclylalkyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl,        (poly-ethylene-glycol)-ethyl, and an optionally substituted        saccharide;        -   or R⁴ and R⁵ taken together form an optionally substituted            heterocycle with the nitrogen to which they are attached;    -   each R¹⁰ is independently selected from the group consisting of        optionally substituted C₁-C₆ alkyl and optionally substituted        C₃-C₆ cycloalkyl;    -   each Y is independently a group comprising 1-50 non-hydrogen        atoms selected from the group consisting of C, N, O, S, and P;        and    -   X is

-   -   J is a 1-4 atom alkylene or 1-4 atom alkenylene, optionally        substituted by one or more substituents selected from the group        consisting of Cl, F, CN, CF₃, —R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, and        —C(═O)OR¹⁹, wherein said 1-4 atom alkylene or 1-4 atom        alkenylene is optionally fused to an optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        carbocyclyl, or optionally substituted heterocyclyl;    -   R³ is selected from the group consisting of R³¹, —(R³⁰)_(q)OR³¹,        —(R³⁰)_(q)O(R³⁰)_(q)OR³¹, R³⁰OC(O)R³¹, —R³⁰OC(O)OR³¹,        —R³⁰OC(O)NHR³¹, —R³⁰OC(O)N(R³¹)₂, optionally substituted        alkyloxyalkyl, optionally substituted acyloxyalkyl, optionally        substituted alkyloxycarbonyloxyalkyl, optionally substituted        cycloalkyloxycarbonyloxyalkyl, optionally substituted        aryloxycarbonyloxyalkyl, and optionally substituted        alkyl-[1,3]dioxol-2-one;    -   each R³⁰ is independently —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, or        optionally substituted 1,1′-cyclopropylene;

R³¹ is selected from the group consisting of optionally substitutedC₁-C₁₂ alkyl, optionally substituted C₁-C₁₂ alkenyl, optionallysubstituted C₁-C₁₂ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted alkylcycloalkyl, optionally substitutedalkylheterocycloalkyl, optionally substituted alkylaryl, and optionallysubstituted alkylheteroaryl; each q is independently 2, 3, 4, 5, or 6;

-   -   R¹⁶ is selected from a group consisting of H, —C₁-C₉alkyl,        —C₂-C₉alkenyl, —C₂-C₉alkynyl, carbocyclyl, —C₁-C₉alkylR²¹,        —C₂-C₉alkenylR²¹, —C₂-C₉alkynylR²¹, carbocyclylR²¹, —C(═O)OR¹⁹,        —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,        —C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or alternatively:        -   (i) R¹⁶ and an R¹⁷ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (ii) R¹⁶ and a carbon atom in J are taken together with            intervening atoms to form a substituted or unsubstituted            carbocyclyl or substituted or unsubstituted heterocyclyl, or        -   (iii) R¹⁶ is absent when the carbon to which it is attached            is a ring atom in an aryl or heteroaryl ring;    -   each R¹⁷ is independently selected from a group consisting of H,        halo, —C₁-C₉alkyl, —C₂-C₉alkenyl, —C₂-C₉alkynyl, NR¹⁹R²⁰, —OR¹⁹,        —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,        —C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or independently:        -   (i) R¹⁶ and an R¹⁷ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (ii) R¹⁷ and an R¹⁸ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (iii) an R¹⁷ and a carbon atom in J are taken together with            intervening atoms to form a substituted or unsubstituted            carbocyclyl or substituted or unsubstituted heterocyclyl;    -   each R¹⁸ is independently selected from a group consisting of H,        halo, —C₂-C₉alkenyl, —C₂-C₉alkynyl, NR¹⁹R²⁰, —OR¹⁹,        —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,        —C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or independently:        -   (i) an R¹⁷ and an R¹⁸ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (ii) a geminal R¹⁷ and R¹⁸ together form            —C₂-C₉alkenylC(═O)OR¹⁹, or        -   (iii) each R¹⁸ attached to a ring atom forming part of a            substituted or unsubstituted aryl is absent;    -   each R¹⁹ is independently selected from a group consisting of H,        —C₁-C₉alkyl, —C₂-C₉alkenyl, —C₂-C₉alkynyl, carbocyclyl,        —C₁-C₉alkylR²¹, —C₂-C₉alkenylR²¹, —C₂-C₉alkynylR²¹,        carbocyclylR²¹, substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, substituted or unsubstituted        carbocyclyl, and substituted or unsubstituted heterocyclyl;    -   each R²⁰ is independently selected from a group consisting of H,        —C₁-C₉alkyl, —OR¹⁹, —CH(═NH), —C(═O)OR¹⁹, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted carbocyclyl, and substituted or        unsubstituted heterocyclyl;    -   each R²¹ is independently selected from a group consisting of        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted carbocyclyl, and        substituted or unsubstituted heterocyclyl; and    -   r is 0 or 1,    -   wherein each —C₁-C₉alkyl, —C₂-C₉alkenyl, and —C₂-C₉alkynyl is        independently optionally substituted.

In some embodiments is a compound of Formula I, wherein X is

and R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃, —R¹⁹,—OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is a compoundof Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is acompound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is acompound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein X is

and R²² and R²⁴ are independently H, Cl, F, CN, CF₃, —R¹⁹, —OR¹⁹,—C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is a compound ofFormula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²² and R²⁴ areH.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, and R²⁴ are independently H, Cl, F, CN, CF₃, —R¹⁹,—OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is a compoundof Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, andR²⁴ are H.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is acompound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein R¹⁶, R¹⁷, andR¹⁸ are H.

In some embodiments is a compound of Formula I, wherein R^(d) ishydrogen or C₁-C₄-alkyl. In some embodiments is a compound of Formula I,wherein R^(d) is hydrogen.

In some embodiments is a compound of Formula I, wherein Z is —C(═O)—.

In some embodiments is a compound of Formula I, wherein n is 0. In someembodiments is a compound of Formula I, wherein n is 1, and R¹ and R²are hydrogen.

In some embodiments is a compound of Formula I, wherein M is a bond.

In some embodiments is a compound of Formula I, wherein m is 0.

In some embodiments is a compound of Formula I, wherein L is a bond.

In some embodiments is a compound of Formula I, wherein A is HetA. Insome embodiments is a compound of Formula I, wherein HetA is selectedfrom the group consisting of azetidine, oxetane, thietane, pyrrolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,imidazolidine, pyrazolidine, 2,5-dihydro-1H-pyrrole,3,4-dihydro-2H-pyrrole, 4,5-dihydrooxazole, 4,5-dihydroisoxazole,4,5-dihydrothiazole, 4,5-dihydroisothiazole, 4,5-dihydro-1H-pyrazole,4,5-dihydro-1H-imidazole, 2,5-dihydro-1H-pyrrole, piperidine,morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydropyran,tetrahydrofuran, 1,4-oxathiane, piperazine, hexahydropyrimidine,hexahydropyridazine, 1,4,5,6-tetrahydropyrimidine, 1,3-oxazinane,5,6-dihydro-4H-1,3-oxazine, 1,3-thiazinane, 5,6-dihydro-4H-1,3-thiazine,1,4,5,6-tetrahydropyridazine, 1,2,3,6-tetrahydropyrazine,1,2,3,6-tetrahydropyridine, 1,2,3,6-tetrahydropyridazine, azepane,1,3-oxazepane, 1,4-oxazepane, 1,3-diazepane, 1,4-diazepane,1,3-thiazepane, 1,4-thiazepane, diazepane, oxazepane, thiazepane,3,4,5,6-tetrahydro-2H-azepine, 4,5,6,7-tetrahydro-1H-1,3-diazepine,4,5,6,7-tetrahydro-1,3-oxazepine, 4,5,6,7-tetrahydro-1,3-thiazepine,2,3,4,7-tetrahydro-1H-1,3-diazepine, and2,3,4,7-tetrahydro-1,3-oxazepine. In some embodiments is a compound ofFormula I, wherein HetA is selected from the group consisting ofpiperidine, piperazine, pyrrolidine, tetrahydropyran, andtetrahydrofuran.

In some embodiments is a compound of Formula I, wherein A is CycA. Insome embodiments is a compound of Formula I, wherein CycA is cyclohexyl.

In some embodiments is a compound of Formula I, wherein A is ArA. Insome embodiments is a compound of Formula I, wherein ArA is phenyl. Insome embodiments is a compound of Formula I, wherein ArA is pyridyl.

In some embodiments is a compound of Formula I, wherein each Y, providedY is not attached directly to a heteroatom of HetA, is selected from thegroup consisting of:

-   -   fluoro, chloro, bromo, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₃-C₆ cycloalkyl, optionally substituted        heterocycle, optionally substituted aryl, optionally substituted        heteroaryl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,        —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵,        —S(O)_(0,1,2)(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,        —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,        —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)OR¹⁰,        —NR⁴(CR⁶R⁷)_(v)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,        —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,        —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,        —N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,        —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,        —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,        —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,        —O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —S(O)_(0,1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,        —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,        —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,        —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,        —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —S(O)_(0,1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶,        —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵,        —SO₂NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,        -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,        —N(R⁴)—Heteroaryl-NR⁴R⁵, —N(R⁴)—Heterocyclyl-NR⁴R⁵,        —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,        —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,        —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,        —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl,        —O-Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)Heteroaryl,        —NR⁴(CR⁶R⁷)_(v)Heterocyclyl, —O(CR⁶R⁷)_(v)Heteroaryl,        —O(CR⁶R⁷)_(v)Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)NR⁵-Heteroaryl,        —NR⁴(CR⁶R⁷)_(v)NR⁵-Heterocyclyl, —O(CR⁶R⁷)_(v)NR⁵-Heteroaryl,        —O(CR⁶R⁷)_(v)NR⁵-Heterocyclyl, —O(CR⁶R⁷)_(v)O-Heterocyclyl,        —NR⁴R⁵R⁹⁺Q⁻, —(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻,        —NR⁴R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂, —(CR⁶R⁷)_(v)(T)⁺Q⁻, and        —O(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻;    -   wherein:        -   T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl;        -   Q is a pharmaceutically acceptable counterion;        -   each R⁶ and R⁷ are independently selected from the group            consisting of hydrogen, fluoro, chloro, bromo, optionally            substituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl,            optionally substituted hydroxyalkyl, optionally substituted            C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵,            —C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionally substituted heterocyclyl,            optionally substituted aryl, and optionally substituted            heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;        -   R⁹ is optionally substituted C₁-C₆ alkyl; and        -   v is 1-4;    -   or two Ys taken together with the carbon atoms to which they are        attached form an optionally substituted carbocycle, an        optionally substituted heterocycle, or a carbonyl group; or    -   in the case where Y is attached directly to a heteroatom of        HetA, Y is selected from the group consisting of:        -   —(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(1,2)(CR⁶R⁷)_(v)NR⁴R⁵,            —C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(w)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(w)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(w)OR¹⁰,            —(CR⁶R⁷)_(w)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵,            —S(O)_(1,2)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵, —C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —C(═NR⁵)R⁶, —(CR⁶R⁷)_(w)N(R⁴)C(═NR⁵)R⁶,            —S(O)_(1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(w)C(═NR⁵)NR⁴R⁵,            —S(O)_(1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(w)N(R⁴)C(═NR⁵)NR⁴R⁵,            —S(O)_(1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —S(O)_(1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶, —SO₂R⁶, —C(O)R⁶,            —C(═O)OR⁶, —C(O)NR⁴R⁵, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵,            -aryl, -heteroaryl, —C(O)N(R⁴)—Heteroaryl-NR⁴R⁵,            -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,            -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heteroaryl-NR⁴R⁵,            -Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl,            —(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —(CR⁶R⁷)_(v)O-Heterocyclyl, —R⁹⁺Q⁻, —(CR⁶R⁷)_(w)NR⁴R⁵R⁹⁺Q⁻,            —R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂ and —(CR⁶R⁷)_(v)(T)⁺Q;    -   wherein:        -   T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl;        -   Q is a pharmaceutically acceptable counterion;        -   each R⁶ and R⁷ are independently selected from the group            consisting of hydrogen, fluoro, chloro, bromo, optionally            substituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl,            optionally substituted hydroxyalkyl, optionally substituted            C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵,            —C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionally substituted heterocyclyl,            optionally substituted aryl, and optionally substituted            heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;        -   R⁹ is optionally substituted C₁-C₆ alkyl;        -   v is 1-4; and        -   w is 2-4.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of fluoro, chloro, —CN, optionallysubstituted C₁-C₆ alkyl, —OH, —OR¹⁰, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴C(═NR⁵)NR⁴C(═NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═N(═NR⁴)NR⁴R⁵,—O(CR⁶R⁷))_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,—(CR⁶R⁷)_(v)C(O)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,-Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,—N(R⁴)—Heteroaryl-NR⁴R⁵, —N(R⁴)—Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl,—(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, —NR⁴(CR⁶R⁷)_(v)Heterocyclyl,—O(CR⁶R⁷)_(v)Heteroaryl, —O(CR⁶R⁷)_(v)Heterocyclyl, and—O(CR⁶R⁷)_(v)O-Heterocyclyl.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of fluoro, chloro, —CN, optionallysubstituted C₁-C₆ alkyl, —OH, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴C(O)R⁶, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl, and—NR⁴(CR⁶R⁷)_(v)Heterocyclyl.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of —NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵,—C(═NR⁴)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)OR¹⁰, —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,NR⁵C(═NR⁵)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁵C(O)CR⁶(NR⁴R⁵)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, and —O(CR⁶R⁷)_(v)NR⁴R⁵.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of -Heteroaryl-NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,-Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,—N(R⁴)—Heterocyclyl-NR⁴R⁵, -Heteroaryl-C(═NR⁵)NR⁴R⁵,-Heterocyclyl-C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, and—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵.

In some embodiments is a compound of Formula I, wherein at least one Yis 2-(NR⁴R⁵)-pyridyl, 2-(NR⁴R⁵)-pyrimidinyl, 2-(NR⁴R⁵)-thiazolyl,2-(NR⁴R⁵)-imidazolyl, 3-(NR⁴R⁵)-pyrazolyl, 3-(NR⁴R⁵)-isothiazolyl,2-(NR⁴R⁵)-oxazolyl, piperidine, pyrrolidine, 4-amino-piperidinyl,3-amino-pyrrolidinyl, piperazine, or 4-carboximidoyl-piperazinyl.

In some embodiments is a compound of Formula I, wherein two Y groups,together with the atoms to which they are attached form a pyrrolidinering.

In some embodiments is a compound of Formula I, wherein p is 1 or 2.

In some embodiments is a compound of Formula I, wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl, optionallysubstituted hydroxyalkyl, and optionally substituted heterocyclyl. Insome embodiments is a compound of Formula I, wherein R⁴ and R⁵ areindependently hydrogen or optionally substituted C₁-C₆ alkyl.

In some embodiments is a compound of Formula I, wherein R⁶ and R⁷ areindependently selected from the group consisting of hydrogen, halogen,optionally substituted C₁-C₆ alkyl, —OH, —NR⁴R⁵, and optionallysubstituted heterocyclyl, or R⁶ and R⁷ taken together form an optionallysubstituted heterocycle with the carbon to which they are attached. Insome embodiments some embodiments is a compound of Formula I, wherein R⁶and R⁷ are independently hydrogen, fluoro, or optionally substitutedC₁-C₆ alkyl.

In some embodiments is a compound of Formula I, wherein R³ is H.

In some embodiments is a compound of Formula I, wherein R³ is R³¹. Insome embodiments is a compound of Formula I, wherein R³ is C₁-C₁₂ alkyl.In some embodiments is a compound of Formula I, wherein R³ is methyl,ethyl, propyl, butyl, or isopropyl.

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting optionally substituted C₁-C₁₂ alkenyl,optionally substituted C₁-C₁₂ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈heterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkylcycloalkyl, optionallysubstituted alkylheterocycloalkyl, optionally substituted alkylaryl, andoptionally substituted alkylheteroaryl.

In some embodiments is a compound of Formula I, wherein R³ is optionallysubstituted C₁-C₁₂ alkyl, alkyloxyalkyl, acyloxyalkyl,alkyloxycarbonyloxyalkyl, cycloalkyloxycarbonyloxyalkyl,aryloxycarbonyloxyalkyl, or alkyl-[1,3]dioxol-2-one. In some embodimentsis a compound of Formula I, wherein R³ is acyloxyalkyl. In someembodiments is a compound of Formula I, wherein R³ is —CH₂OC(═O)CH₃ or—CH₂OC(═O)C(CH₃)₃.

In some embodiments is a compound of Formula I, wherein R³ is—(R³⁰)_(q)OR³¹ or —(R³⁰)_(q)O(R³⁰)_(q)OR³¹.

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting of —R³⁰OC(O)R³¹, —R³⁰OC(O)OR³¹,—R³⁰OC(O)NHR³¹, and —R³⁰OC(O)N(R³¹)₂.

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting of:

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting of methyl, ethyl, butyl, pivaloyloxymethyl,acetoxymethyl, ethoxycarbonyloxymethyl, 1-(acetoxy)ethyl,1-(pivaloyloxy)ethyl, 1-(isopropoxycarbonyoxy)ethyl, and1-cyclohexyloxycarbonyloxymethyl.

In certain embodiments of a compound of Formula I, the compound isselected from the group represented by the following structures:

or a pharmaceutically acceptable salt, N-oxide, or isomer thereof.

In another aspect, provided herein, is a pharmaceutical compositioncomprising a compound of Formula I or a pharmaceutically acceptablesalt, N-oxide, or isomer thereof, and a pharmaceutically acceptableexcipient. In some embodiments is a pharmaceutical composition ofFormula I, further comprising a beta-lactam antibiotic. In someembodiments is a pharmaceutical composition of Formula I, furthercomprising a beta-lactam antibiotic wherein the beta-lactam antibioticis a penicillin, cephalosporin, carbapenem, monobactam, bridgedmonobactam, or a combination thereof.

In some embodiments, the compound of Formula I is the stereoisomerrepresented by any of the structures shown herein. In some embodiments,the compound of Formula I is an enantiomer of the stereoisomerrepresented by any of the structures shown herein. In certainembodiments, the compound of Formula I is a diastereomer of thestereoisomer represented by any of the structures shown herein. In someembodiments, the compound of Formula I is a mixture of enantiomersand/or diastereomers of the stereoisomer represented by any of thestructures shown herein. In certain embodiments, the compound of FormulaI is a racemate of the stereoisomer represented by any of the structuresherein.

In a further aspect, provided herein are methods of treating a bacterialinfection in a subject, comprising administering to the subject acompound of Formula I as described herein, optionally in combinationwith a beta-lactam antibiotic. In some embodiments, provided herein, aremethods of treating a bacterial infection in a subject, comprisingadministering to the subject a compound of Formula I as describedherein. In some embodiments, provided herein, are methods of treating abacterial infection in a subject, comprising administering to thesubject a compound of Formula I as described herein in combination witha therapeutically effective amount of beta-lactam antibiotic. In someembodiments, provided herein, are methods of treating a bacterialinfection in a subject, comprising administering to the subject acompound of Formula I as described herein in combination with atherapeutically effective amount of beta-lactam antibiotic wherein thebeta-lactam antibiotic is a penicillin, cephalosporin, carbapenem,monobactam, bridged monobactam, or a combination thereof.

In a further aspect, provided herein are methods of treating a bacterialinfection in a subject, comprising administering to the subject apharmaceutical composition as described herein, optionally incombination with a beta-lactam antibiotic. In some embodiments, providedherein are methods of treating a bacterial infection in a subject,comprising administering to the subject a pharmaceutical composition asdescribed herein. In some embodiments, the methods of treating abacterial infection in a subject comprise administering to the subject apharmaceutical composition as described herein in combination with abeta-lactam antibiotic. In some embodiments, the methods of treating abacterial infection in a subject comprise administering to the subject apharmaceutical composition as described herein in combination with abeta-lactam antibiotic wherein the beta-lactam antibiotic is apenicillin, cephalosporin, carbapenem, monobactam, bridged monobactam,or a combination thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

Beta-lactamases are typically grouped into 4 classes: Ambler classes A,B, C, and D, based on their amino acid sequences. Enzymes in classes A,C, and D are active-site serine beta-lactamases, while class B enzymesare Zn-dependent. Newer generation cephalosporins and carbapenems weredeveloped partly based on their ability to evade the deactivating effectof the early serine-based beta-lactamase variants. However, a recentsurge in new versions of serine-based beta-lactamases—for example ClassA Extended-Spectrum Beta-Lactamase (ESBL) enzymes, Class Acarbapenemases (e.g. KPC-2), chromosomal and plasmid mediated Class Ccephalosporinases (AmpC, CMY, etc.), and Class D oxacillinases—as wellas Class B metallo-beta-lactamases (e.g. VIM, NDM) has begun to diminishthe utility of the beta-lactam antibiotic family, including the morerecent generation beta-lactam drugs, leading to a serious medicalproblem. Indeed the number of catalogued serine-based beta-lactamaseshas exploded from less than ten in the 1970s to over 750 variants (see,e.g., Jacoby & Bush, “Amino Acid Sequences for TEM, SHV and OXAExtended-Spectrum and Inhibitor Resistant β-Lactamases”, on the LaheyClinic website).

The commercially available beta-lactamase inhibitors (clavulanic acid,sulbactam, tazobactam) were developed to address the beta-lactamasesthat were clinically relevant in the 1970s and 1980s (e.g.penicillinases). These beta-lactamase inhibitors are poorly activeagainst the diversity of beta-lactamse enzymes (both serine- andmetallo-based) now emerging clinically. In addition, these enzymeinhibitors are available only as fixed combinations with penicillinderivatives. No combinations with cephalosporins (or carbapenems) areclinically available. This fact, combined with the increased use ofnewer generation cephalosporins and carbapenems, is driving theselection and spread of the new beta-lactamase variants (ESBLs,carbapenemases, chromosomal and plasmid-mediated Class C, Class Doxacillinases, etc.). While maintaining good inhibitory activity againstESBLs, the legacy beta-lactamase inhibitors are largely ineffectiveagainst the new Class A and Class B carbapenemases, against thechromosomal and plasmid-mediated Class C cephalosporinases and againstmany of the Class D oxacillinases.

To address this growing therapeutic vulnerability, and because there arethree major molecular classes of serine-based beta-lactamases, and onemajor class of metallo-beta-lactamases, and each of these classescontains significant numbers of beta-lactamase variants, we haveidentified an approach for developing novel beta-lactamase inhibitorswith broad spectrum functionality. In particular, we have identified anapproach for developing compounds that are active against both serine-and metallo-based beta-lactamase enzymes. Compounds of the currentinvention demonstrate potent activity across all four major classes ofbeta-lactamases.

The present invention is directed to certain boron-based compounds(boronic acids and cyclic boronic acid esters) which are beta-lactamaseinhibitors and antibacterial compounds. The compounds and theirpharmaceutically acceptable salts are useful alone and in combinationwith beta-lactam antibiotics for the treatment of bacterial infections,particularly antibiotic resistant bacterial infections. Some embodimentsinclude compounds, compositions, pharmaceutical compositions, use andpreparation thereof.

DEFINITIONS

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the invention maybe practiced without these details. In other instances, well-knownstructures have not been shown or described in detail to avoidunnecessarily obscuring descriptions of the embodiments. Unless thecontext requires otherwise, throughout the specification and claimswhich follow, the word “comprise” and variations thereof, such as,“comprises” and “comprising” are to be construed in an open, inclusivesense, that is, as “including, but not limited to.” Further, headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. Thus, the appearances of the phrases “in one embodiment” or“in an embodiment” in various places throughout this specification arenot necessarily all referring to the same embodiment. Furthermore, theparticular features, structures, or characteristics may be combined inany suitable manner in one or more embodiments. Also, as used in thisspecification and the appended claims, the singular forms “a,” “an,” and“the” include plural referents unless the content clearly dictatesotherwise. It should also be noted that the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

The term “antibiotic” refers to a compound or composition whichdecreases the viability of a microorganism, or which inhibits the growthor proliferation of a microorganism. The phrase “inhibits the growth orproliferation” means increasing the generation time (i.e., the timerequired for the bacterial cell to divide or for the population todouble) by at least about 2-fold. Preferred antibiotics are those whichcan increase the generation time by at least about 10-fold or more(e.g., at least about 100-fold or even indefinitely, as in total celldeath). As used in this disclosure, an antibiotic is further intended toinclude an antimicrobial, bacteriostatic, or bactericidal agent.Examples of antibiotics suitable for use with respect to the presentinvention include penicillins, cephalosporins and carbapenems.

The term “β-lactam antibiotic” refers to a compound with antibioticproperties that contains a β-lactam functionality. Non-limiting examplesof β-lactam antibiotics useful with respect to the invention includepenicillins, cephalosporins, penems, carbapenems, and monobactams.

The term “β-lactamase” denotes a protein capable of inactivating aβ-lactam antibiotic. The β-lactamase can be an enzyme which catalyzesthe hydrolysis of the β-lactam ring of a β-lactam antibiotic. Ofparticular interest herein are microbial β-lactamases. The β-lactamasemay be, for example, a serine β-lactamase or a metallo-β-lactamase.β-Lactamases of interest include those disclosed in an ongoing websitethat monitors beta-lactamase nomenclature (www.lahey.org) and in Bush,K. and G. A. Jacoby. 2010. An updated functional classification ofβ-lactamases. Antimicrob. Agents Chemother. 54:969-976. β-Lactamases ofparticular interest herein include β-lactamases found in bacteria suchas class A β-lactamases including the SHV, CTX-M and KPC subclasses,class B β-lactamases such as VIM, class C β-lactamases (both chromosomaland plasmid-mediated), and class D β-lactamases. The term “β-lactamaseinhibitor” refers to a compound which is capable of inhibitingβ-lactamase activity. Inhibiting β-lactamase activity means inhibitingthe activity of a class A, B, C, or D β-lactamase. For antimicrobialapplications inhibition at a 50% inhibitory concentration is preferablyachieved at or below about 100 micrograms/mL, or at or below about 50micrograms/mL, or at or below about 25 micrograms/mL. The terms “classA”, “class B”, “class C”, and “class D” β-lactamases are understood bythose skilled in the art and are described in Bush, K. and G. A. Jacoby.2010. An updated functional classification of β-lactamases. Antimicrob.Agents Chemother. 54:969-976.

The terms below, as used herein, have the following meanings, unlessindicated otherwise:

“Amino” refers to the —NH₂ radical.

“Cyano” or “nitrile” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Oxime” refers to the ═N—OH substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain saturated hydrocarbon monoradicalhaving from one to about ten carbon atoms, more preferably one to sixcarbon atoms, wherein an sp3-hybridized carbon of the alkyl residue isattached to the rest of the molecule by a single bond. Examples include,but are not limited to methyl, ethyl, n-propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or“C₁₋₆ alkyl”, means that the alkyl group may consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbonatoms, although the present definition also covers the occurrence of theterm “alkyl” where no numerical range is designated. Unless statedotherwise specifically in the specification, an alkyl group may beoptionally substituted as described below, for example, with oxo, amino,nitrile, nitro, hydroxyl, alkyl, alkylene, alkynyl, alkoxy, aryl,cycloalkyl, heterocyclyl, heteroaryl, and the like.

“Alkenyl” refers to an optionally substituted straight-chain, oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon double-bonds and having from two to about tencarbon atoms, more preferably two to about six carbon atoms, wherein ansp2-hybridized carbon of the alkenyl residue is attached to the rest ofthe molecule by a single bond. The group may be in either the cis ortrans conformation about the double bond(s), and should be understood toinclude both isomers. Examples include, but are not limited to ethenyl(—CH═CH₂), 1-propenyl (—CH₂CH═CH₂), isopropenyl [—C(CH₃)═CH₂], butenyl,1,3-butadienyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkenyl” or “C₂₋₆ alkenyl”, means that the alkenylgroup may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkenyl” where no numerical range isdesignated.

“Alkynyl” refers to an optionally substituted straight-chain oroptionally substituted branched-chain hydrocarbon monoradical having oneor more carbon-carbon triple-bonds and having from two to about tencarbon atoms, more preferably from two to about six carbon atoms.Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl,1,3-butadiynyl and the like. Whenever it appears herein, a numericalrange such as “C₂-C₆ alkynyl” or “C₂₋₆ alkynyl”, means that the alkynylgroup may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5carbon atoms or 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkynyl” where no numerical range isdesignated.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain. Unless stated otherwise specifically in thespecification, an alkylene group may be optionally substituted asdescribed below.

“Alkoxy” or “alkyloxy” refers to a radical of the formula —OR_(a) whereR_(a) is an alkyl radical as defined. Unless stated otherwisespecifically in the specification, an alkoxy group may be optionallysubstituted as described below.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from the hydrocarbon ring systems of aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals that are optionally substituted.

“Cycloalkyl” or “carbocyclyl” or “carbocycle” refers to a stable,non-aromatic, monocyclic or polycyclic carbocyclic ring, which mayinclude fused or bridged ring systems, which is saturated orunsaturated. Representative cycloalkyls or carbocycles include, but arenot limited to, cycloalkyls having from three to fifteen carbon atoms,from three to ten carbon atoms, from three to eight carbon atoms, fromthree to six carbon atoms, from three to five carbon atoms, or three tofour carbon atoms. Monocyclic cycloalkyls or carbocycles include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, forexample, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane,bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, andbicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unlessotherwise stated specifically in the specification, a cycloalkyl orcarbocycle group may be optionally substituted. Illustrative examples ofcycloalkyl groups include, but are not limited to, the followingmoieties:

and the like.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heterocyclyl ringor a heteroaryl ring, any carbon atom on the existing ring structurewhich becomes part of the fused heterocyclyl ring or the fusedheteroaryl ring may be replaced with a nitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Haloalkoxy” similarly refers to a radical of the formula —OR_(a) whereR_(a) is a haloalkyl radical as defined. Unless stated otherwisespecifically in the specification, a haloalkoxy group may be optionallysubstituted as described below.

“Heterocycloalkyl” or “heterocyclyl” or “heterocyclic ring” or“heterocycle” refers to a stable 3- to 24-membered non-aromatic ringradical comprising 2 to 23 carbon atoms and from one to 8 heteroatomsselected from the group consisting of nitrogen, oxygen, phosphorous andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquatemized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 12-crown-4,15-crown-5, 18-crown-6, 21-crown-7, aza-18-crown-6, diaza-18-crown-6,aza-21-crown-7, and diaza-21-crown-7. Unless stated otherwisespecifically in the specification, a heterocyclyl group may beoptionally substituted. Illustrative examples of heterocycloalkylgroups, also referred to as non-aromatic heterocycles, include:

and the like. The term heterocycloalkyl also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl group may be optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. For purposes ofthis invention, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused or bridgedring systems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group may be optionallysubstituted.

All the above groups may be either substituted or unsubstituted. Theterm “substituted” as used herein means any of the above groups (e.g,alkyl, alkylene, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyland/or heteroaryl) may be further functionalized wherein at least onehydrogen atom is replaced by a bond to a non-hydrogen atom substituent.Unless stated specifically in the specification, a substituted group mayinclude one or more substituents selected from: oxo, amino, —CO₂H,nitrile, nitro, hydroxyl, thiooxy, alkyl, alkylene, alkoxy, aryl,cycloalkyl, heterocyclyl, heteroaryl, dialkylamines, arylamines,alkylarylamines, diarylamines, trialkylammonium (—N⁺R₃), N-oxides,imides, and enamines; a silicon atom in groups such as trialkylsilylgroups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilylgroups, perfluoroalkyl or perfluoroalkoxy, for example, trifluoromethylor trifluoromethoxy. “Substituted” also means any of the above groups inwhich one or more hydrogen atoms are replaced by a higher-order bond(e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo,carbonyl, carboxyl, and ester groups; and nitrogen in groups such asimines, oximes, hydrazones, and nitriles. For example, “substituted”includes any of the above groups in which one or more hydrogen atoms arereplaced with —NH₂, —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)NR_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h). Inthe foregoing, R_(g) and R_(h) are the same or different andindependently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl. In addition, each of the foregoing substituents mayalso be optionally substituted with one or more of the abovesubstituents. Furthermore, any of the above groups may be substituted toinclude one or more internal oxygen, sulfur, or nitrogen atoms. Forexample, an alkyl group may be substituted with one or more internaloxygen atoms to form an ether or polyether group. Similarly, an alkylgroup may be substituted with one or more internal sulfur atoms to forma thioether, disulfide, etc.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined above.Further, an optionally substituted group may be un-substituted (e.g.,—CH₂CH₃), fully substituted (e.g., —CF₂CF₃), mono-substituted (e.g.,—CH₂CH₂F) or substituted at a level anywhere in-between fullysubstituted and mono-substituted (e.g., —CH₂CHF₂, —CH₂CF₃, —CF₂CH₃,—CFHCHF₂, etc). It will be understood by those skilled in the art withrespect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitutionpatterns (e.g., substituted alkyl includes optionally substitutedcycloalkyl groups, which in turn are defined as including optionallysubstituted alkyl groups, potentially ad infinitum) that are stericallyimpractical and/or synthetically non-feasible. Thus, any substituentsdescribed should generally be understood as having a maximum molecularweight of about 1,000 daltons, and more typically, up to about 500daltons.

An “effective amount” or “therapeutically effective amount” refers to anamount of a compound administered to a mammalian subject, either as asingle dose or as part of a series of doses, which is effective toproduce a desired therapeutic effect.

“Treatment” of an individual (e.g. a mammal, such as a human) or a cellis any type of intervention used in an attempt to alter the naturalcourse of the individual or cell. In some embodiments, treatmentincludes administration of a pharmaceutical composition, subsequent tothe initiation of a pathologic event or contact with an etiologic agentand includes stabilization of the condition (e.g., condition does notworsen) or alleviation of the condition. In other embodiments, treatmentalso includes prophylactic treatment (e.g., administration of acomposition described herein when an individual is suspected to besuffering from a bacterial infection).

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The compounds presented herein mayexist as tautomers. Tautomers are compounds that are interconvertible bymigration of a hydrogen atom, accompanied by a switch of a single bondand adjacent double bond. In bonding arrangements where tautomerizationis possible, a chemical equilibrium of the tautomers will exist. Alltautomeric forms of the compounds disclosed herein are contemplated. Theexact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Some examples of tautomericinterconversions include:

Compounds

Described herein are compounds that modulate the activity ofbeta-lactamase. In some embodiments, the compounds described hereininhibit beta-lactamase. In certain embodiments, the compounds describedherein are useful in the treatment of bacterial infections. In someembodiments, the bacterial infection is an upper or lower respiratorytract infection, a urinary tract infection, an intra-abdominalinfection, or a skin infection.

In one aspect, provided herein are compounds of Formula I orpharmaceutically acceptable salts, tautomers, or N-oxides thereof:

wherein:

-   -   L is a bond, —C(R¹R²)—, —C(═O)—, or ═C(R¹)—;    -   M is a bond, —O—, —S—, —S(O)—, —S(O)₂—, or —N(R⁴)—;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, 3, or 4;    -   Z is —C(═O)—, —C(═S), or —S(O)₂—;    -   A is CycA, ArA or HetA, wherein        -   CycA is an optionally substituted 3-10 membered non-aromatic            carbocycle, wherein an optional olefin functionality of the            non-aromatic carbocycle is not directly attached to an            oxygen, sulfur, or nitrogen substituent;        -   ArA is an aromatic or heteroaromatic ring system optionally            substituted with one or more substituents selected from the            group consisting of fluoro, chloro, bromo, —CN, optionally            substituted C₁-C₆ alkyl, optionally substituted C₃-C₆            cycloalkyl, optionally substituted heterocycle, optionally            substituted aryl, optionally substituted heteroaryl, —OH,            —OR¹⁰, and —SR¹⁰;        -   HetA is an optionally substituted non-aromatic heterocyclic            ring system;    -   each R¹ and R² is independently selected from the group        consisting of hydrogen, fluoro, chloro, bromo, optionally        substituted C₁-C₆ alkyl, optionally substituted C₃-C₆        cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, and —NR⁴R⁵,        -   or R¹ and R² taken together form an oxo, oxime, or an            optionally substituted carbocycle        -   or optionally substituted heterocycle with the carbon to            which they are attached;    -   each R^(d), R⁴, and R⁵ is independently selected from the group        consisting of hydrogen, —OH, —CN, optionally substituted C₁-C₆        alkyl, optionally substituted alkoxyalkyl, optionally        substituted hydroxyalkyl, optionally substituted aminoalkyl,        optionally substituted cycloalkyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted cycloalkylalkyl,        optionally substituted heterocyclylalkyl, optionally substituted        aralkyl, optionally substituted heteroaralkyl,        (poly-ethylene-glycol)-ethyl, and an optionally substituted        saccharide;        -   or R⁴ and R⁵ taken together form an optionally substituted            heterocycle with the nitrogen to which they are attached;    -   each R¹⁰ is independently selected from the group consisting of        optionally substituted C₁-C₆ alkyl and optionally substituted        C₃-C₆ cycloalkyl;    -   each Y is independently a group comprising 1-50 non-hydrogen        atoms selected from the group consisting of C, N, O, S, and P;        and    -   X is

-   -   J is a 1-4 atom alkylene or 1-4 atom alkenylene, optionally        substituted by one or more substituents selected from the group        consisting of Cl, F, CN, CF₃, —R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, and        —C(═O)OR¹⁹, wherein said 1-4 atom alkylene or 1-4 atom        alkenylene is optionally fused to an optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        carbocyclyl, or optionally substituted heterocyclyl;    -   R³ is selected from the group consisting of R³¹, —(R³⁰)_(q)OR³¹,        —(R³⁰)_(q)O(R³⁰)_(q)OR³¹, —R³⁰OC(O)R³¹, —R³⁰OC(O)OR³,        —R³⁰OC(O)NHR³¹, —R³⁰OC(O)N(R³)₂, optionally substituted        alkyloxyalkyl, optionally substituted acyloxyalkyl, optionally        substituted alkyloxycarbonyloxyalkyl, optionally substituted        cycloalkyloxycarbonyloxyalkyl, optionally substituted        aryloxycarbonyloxyalkyl, and optionally substituted        alkyl-[1,3]dioxol-2-one;    -   each R³⁰ is independently —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, or        optionally substituted 1,1′-cyclopropylene;    -   R³¹ is selected from the group consisting of optionally        substituted C₁-C₁₂ alkyl, optionally substituted C₁-C₁₂ alkenyl,        optionally substituted C, —C₁₂ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈        heterocycloalkyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted alkylcycloalkyl,        optionally substituted alkylheterocycloalkyl, optionally        substituted alkylaryl, and optionally substituted        alkylheteroaryl;    -   each q is independently 2, 3, 4, 5, or 6;    -   R¹⁶ is selected from a group consisting of H, —C₁-C₉alkyl,        —C₂-C₉alkenyl, —C₂-C₉alkynyl, carbocyclyl, —C₁-C₉alkylR²¹,        —C₂-C₉alkenylR²¹, —C₂-C₉alkynylR²¹, carbocyclylR²¹, —C(═O)OR¹⁹,        —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,        —C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or alternatively:        -   (i) R¹⁶ and an R¹⁷ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (ii) R¹⁶ and a carbon atom in J are taken together with            intervening atoms to form a substituted or unsubstituted            carbocyclyl or substituted or unsubstituted heterocyclyl, or        -   (iii) R¹⁶ is absent when the carbon to which it is attached            is a ring atom in an aryl or heteroaryl ring;    -   each R¹⁷ is independently selected from a group consisting of H,        halo, —C₁-C₉alkyl, —C₂-C₉alkenyl, —C₂-C₉alkynyl, NR¹⁹R²⁰, —OR¹⁹,        —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,        —C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or independently:        -   (i) R¹⁶ and an R¹⁷ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (ii) R¹⁷ and an R¹⁸ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (iii) an R¹⁷ and a carbon atom in J are taken together with            intervening atoms to form a substituted or unsubstituted            carbocyclyl or substituted or unsubstituted heterocyclyl;    -   each R¹⁸ is independently selected from a group consisting of H,        halo, —C₂-C₉alkenyl, —C₂-C₉alkynyl, NR¹⁹R²⁰, —OR¹⁹,        —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,        —C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or independently:        -   (i) an R¹⁷ and an R¹⁸ are taken together with the atoms to            which they are attached to form a substituted or            unsubstituted carbocyclyl or substituted or unsubstituted            heterocyclyl,        -   (ii) a geminal R¹⁷ and R¹⁸ together form            —C₂-C₉alkenylC(═O)OR¹⁹, or        -   (iii) each R¹⁸ attached to a ring atom forming part of a            substituted or unsubstituted aryl is absent;    -   each R¹⁹ is independently selected from a group consisting of H,        —C₁-C₉alkyl, —C₂-C₉alkenyl, —C₂-C₉alkynyl, carbocyclyl,        —C₁-C₉alkylR²¹, —C₂-C₉alkenylR²¹, —C₂-C₉alkynylR²¹,        carbocyclylR²¹, substituted or unsubstituted aryl, substituted        or unsubstituted heteroaryl, substituted or unsubstituted        carbocyclyl, and substituted or unsubstituted heterocyclyl;        -   each R²⁰ is independently selected from a group consisting            of H, —C₁-C₉alkyl, —OR¹⁹, —CH(═NH), —C(═O)OR¹⁹, substituted            or unsubstituted aryl, substituted or unsubstituted            heteroaryl, substituted or unsubstituted carbocyclyl, and            substituted or unsubstituted heterocyclyl;        -   each R²¹ is independently selected from a group consisting            of substituted or unsubstituted aryl, substituted or            unsubstituted heteroaryl, substituted or unsubstituted            carbocyclyl, and substituted or unsubstituted heterocyclyl;            and        -   r is 0 or 1,        -   wherein each —C₁-C₉alkyl, —C₂-C₉alkenyl, and —C₂-C₉alkynyl            is independently optionally substituted.

In some embodiments is a compound of Formula I, wherein X is

and R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃, —R¹⁹,—OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is a compoundof Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is acompound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is acompound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein X is

and R²² and R²⁴ are independently H, C, F, CN, CF₃, —R¹⁹, —OR¹⁹,C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is a compound ofFormula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²² and R²⁴ areH.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, and R²⁴ are independently H, Cl, F, CN, CF₃, —R¹⁹,—OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is a compoundof Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, andR²⁴ are H.

In some embodiments is a compound of Formula I, wherein X is

and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. In some embodiments is acompound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein X is

In some embodiments is a compound of Formula I, wherein R²², R²³, R²⁴,and R²⁵ are H.

In some embodiments is a compound of Formula I, wherein R¹⁶, R¹⁷, andR¹⁸ are H.

In some embodiments is a compound of Formula I, wherein R^(d) ishydrogen or C₁-C₄-alkyl. In some embodiments is a compound of Formula I,wherein R^(d) is hydrogen.

In some embodiments is a compound of Formula I, wherein Z is —C(═O)—.

In some embodiments is a compound of Formula I, wherein n is 0. In someembodiments is a compound of Formula I, wherein n is 1, and R¹ and R²are hydrogen.

In some embodiments is a compound of Formula I, wherein M is a bond.

In some embodiments is a compound of Formula I, wherein m is 0.

In some embodiments is a compound of Formula I, wherein L is a bond.

In some embodiments is a compound of Formula I, wherein A is HetA. Insome embodiments is a compound of Formula I, wherein HetA is selectedfrom the group consisting of azetidine, oxetane, thietane, pyrrolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,imidazolidine, pyrazolidine, 2,5-dihydro-1H-pyrrole,3,4-dihydro-2H-pyrrole, 4,5-dihydrooxazole, 4,5-dihydroisoxazole,4,5-dihydrothiazole, 4,5-dihydroisothiazole, 4,5-dihydro-1H-pyrazole,4,5-dihydro-1H-imidazole, 2,5-dihydro-1H-pyrrole, piperidine,morpholine, thiomorpholine, tetrahydrothiopyran, tetrahydropyran,tetrahydrofuran, 1,4-oxathiane, piperazine, hexahydropyrimidine,hexahydropyridazine, 1,4,5,6-tetrahydropyrimidine, 1,3-oxazinane,5,6-dihydro-4H-1,3-oxazine, 1,3-thiazinane, 5,6-dihydro-4H-1,3-thiazine,1,4,5,6-tetrahydropyridazine, 1,2,3,6-tetrahydropyrazine,1,2,3,6-tetrahydropyridine, 1,2,3,6-tetrahydropyridazine, azepane,1,3-oxazepane, 1,4-oxazepane, 1,3-diazepane, 1,4-diazepane,1,3-thiazepane, 1,4-thiazepane, diazepane, oxazepane, thiazepane,3,4,5,6-tetrahydro-2H-azepine, 4,5,6,7-tetrahydro-1H-1,3-diazepine,4,5,6,7-tetrahydro-1,3-oxazepine, 4,5,6,7-tetrahydro-1,3-thiazepine,2,3,4,7-tetrahydro-1H-1,3-diazepine, and2,3,4,7-tetrahydro-1,3-oxazepine. In some embodiments is a compound ofFormula I, wherein HetA is selected from the group consisting ofpiperidine, piperazine, pyrrolidine, tetrahydropyran, andtetrahydrofuran.

In some embodiments is a compound of Formula I, wherein A is CycA. Insome embodiments is a compound of Formula I, wherein CycA is cyclohexyl.

In some embodiments is a compound of Formula I, wherein A is ArA. Insome embodiments is a compound of Formula I, wherein ArA is phenyl. Insome embodiments is a compound of Formula I, wherein ArA is pyridyl.

In some embodiments is a compound of Formula I, wherein each Y, providedY is not attached directly to a heteroatom of HetA, is selected from thegroup consisting of:

-   -   fluoro, chloro, bromo, —CN, optionally substituted C₁-C₆ alkyl,        optionally substituted C₃-C₆ cycloalkyl, optionally substituted        heterocycle, optionally substituted aryl, optionally substituted        heteroaryl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,        —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵,        —S(O)_(0,1,2)(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,        —(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,        —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)OR¹⁰,        —NR⁴(CR⁶R⁷)_(v)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,        —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,        —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,        —N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,        —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,        —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,        —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,        —O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —S(O)_(0,1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,        —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,        —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,        —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,        —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —S(O)_(0,1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,        —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶,        —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵,        —SO₂NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,        -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,        —N(R⁴)—Heteroaryl-NR⁴R⁵, —N(R⁴)—Heterocyclyl-NR⁴R⁵,        —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,        —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,        —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,        —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl,        —O-Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)Heteroaryl,        —NR⁴(CR⁶R⁷)_(v)Heterocyclyl, —O(CR⁶R⁷)_(v)Heteroaryl,        —O(CR⁶R⁷)_(v)Heterocyclyl, —NR⁴(CR⁶R⁷)_(v)NR⁵-Heteroaryl,        —NR⁴(CR⁶R⁷)_(v)NR⁵-Heterocyclyl, —O(CR⁶R⁷)_(v)NR⁵-Heteroaryl,        —O(CR⁶R⁷)_(v)NR⁵-Heterocyclyl, —O(CR⁶R⁷)_(v)O-Heterocyclyl,        —NR⁴R⁵R⁹⁺Q⁻, —(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻,        —NR⁴R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂, —(CR⁶R⁷)_(v)(T)⁺Q⁻, and        —O(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻;    -   wherein:        -   T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl;        -   Q is a pharmaceutically acceptable counterion;        -   each R⁶ and R⁷ are independently selected from the group            consisting of hydrogen, fluoro, chloro, bromo, optionally            substituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl,            optionally substituted hydroxyalkyl, optionally substituted            C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵,            —C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionally substituted heterocyclyl,            optionally substituted aryl, and optionally substituted            heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;        -   R⁹ is optionally substituted C₁-C₆ alkyl; and        -   v is 1-4;    -   or two Ys taken together with the carbon atoms to which they are        attached form an optionally substituted carbocycle, an        optionally substituted heterocycle, or a carbonyl group; or    -   in the case where Y is attached directly to a heteroatom of        HetA, Y is selected from the group consisting of:        -   —(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(1,2)(CR⁶R⁷)_(v)NR⁴R⁵,            —C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(w)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,            —(CR⁶R⁷)_(w)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(w)OR¹⁰,            —(CR⁶R⁷)_(w)S(O)_(0,1,2)R¹⁰, —C(O)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵,            —S(O)_(1,2)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵, —C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,            —C(═NR⁵)R⁶, —(CR⁶R⁷)_(w)N(R⁴)C(═NR⁵)R⁶,            —S(O)_(1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,            —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(w)C(═NR⁵)NR⁴R⁵,            —S(O)_(1,2)(CR⁶R⁷)_(v)C(═NR⁵)N)NR⁴R⁵,            —(CR⁶R⁷)_(w)N(R⁴)C(═NR⁵)NR⁴R⁵,            —S(O)_(1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,            —C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —S(O)_(1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,            —C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶, —SO₂R⁶, —C(O)R⁶,            —C(═O)OR⁶, —C(O)NR⁴R⁵, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵,            -aryl, -heteroaryl, —C(O)N(R⁴)—Heteroaryl-NR⁴R⁵,            -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,            -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heteroaryl-NR⁴R⁵,            -Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,            —(CR⁶R⁷)_(v)Heteroaryl, —(CR⁶R⁷)_(v)Heterocyclyl,            —(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,            —(CR⁶R⁷)_(v)O-Heterocyclyl, —R⁹⁺Q⁻, —(CR⁶R⁷)_(w)NR⁴R⁵R⁹⁺Q⁻,            —R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂ and —(CR⁶R⁷)_(v)(T)⁺Q;    -   wherein:        -   T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl;        -   Q is a pharmaceutically acceptable counterion;        -   each R⁶ and R⁷ are independently selected from the group            consisting of hydrogen, fluoro, chloro, bromo, optionally            substituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl,            optionally substituted hydroxyalkyl, optionally substituted            C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵,            —C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionally substituted heterocyclyl,            optionally substituted aryl, and optionally substituted            heteroaryl;        -   or R⁶ and R⁷ taken together form an oxo, oxime, or an            optionally substituted carbocycle or an optionally            substituted heterocycle with the carbon to which they are            attached;        -   R⁹ is optionally substituted C₁-C₆ alkyl;        -   v is 1-4; and        -   w is 2-4.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of fluoro, chloro, —CN, optionallysubstituted C₁-C₆ alkyl, —OH, —OR¹⁰, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵NR⁴R⁵,—NR⁴C(═NR⁵)NR⁴C(═NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶, —C(O)NR⁴R⁵,—(CR⁶R⁷)_(v)C(O)NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,-Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,—N(R⁴)—Heteroaryl-NR⁴R⁵, —N(R⁴)—Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl,—(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, —NR⁴(CR⁶R⁷)_(v)Heterocyclyl,—O(CR⁶R⁷)_(v)Heteroaryl, —O(CR⁶R⁷)_(v)Heterocyclyl, and—O(CR⁶R⁷)_(v)O-Heterocyclyl.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of fluoro, chloro, —CN, optionallysubstituted C₁-C₆ alkyl, —OH, —NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —NR⁴C(O)R⁶, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heterocyclyl,and —NR⁴(CR⁶R⁷)_(v)Heterocyclyl.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of —NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵,—C(═NR⁴)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)OR¹⁰, —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,NR⁵C(═NR⁵)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—NR⁵C(O)CR⁶(NR⁴R⁵)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶,—NR⁴(CR⁶R⁷)_(v) Heteroaryl, and —O(CR⁶R⁷)_(v)NR⁴R⁵.

In some embodiments is a compound of Formula I, wherein at least one Yis selected from the group consisting of -Heteroaryl-NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,-Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,—N(R⁴)—Heterocyclyl-NR⁴R⁵, -Heteroaryl-C(═NR⁵)NR⁴R⁵,-Heterocyclyl-C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, and—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵.

In some embodiments is a compound of Formula I, wherein at least one Yis 2-(NR⁴R⁵)-pyridyl, 2-(NR⁴R⁵)-pyrimidinyl, 2-(NR⁴R⁵)-thiazolyl,2-(NR⁴R⁵)-imidazolyl, 3-(NR⁴R⁵)-pyrazolyl, 3-(NR⁴R⁵)-isothiazolyl,2-(NR⁴R⁵)-oxazolyl, piperidine, pyrrolidine, 4-amino-piperidinyl,3-amino-pyrrolidinyl, piperazine, or 4-carboximidoyl-piperazinyl.

In some embodiments is a compound of Formula I, wherein two Y groups,together with the atoms to which they are attached form a pyrrolidinering.

In some embodiments is a compound of Formula I, wherein p is 1 or 2.

In some embodiments is a compound of Formula I, wherein R⁴ and R⁵ areindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl, optionallysubstituted hydroxyalkyl, and optionally substituted heterocyclyl. Insome embodiments is a compound of Formula I, wherein R⁴ and R⁵ areindependently hydrogen or optionally substituted C₁-C₆ alkyl.

In some embodiments is a compound of Formula I, wherein R⁶ and R⁷ areindependently selected from the group consisting of hydrogen, halogen,optionally substituted C₁-C₆ alkyl, —OH, —NR⁴R⁵, and optionallysubstituted heterocyclyl, or R⁶ and R⁷ taken together form an optionallysubstituted heterocycle with the carbon to which they are attached. Insome embodiments some embodiments is a compound of Formula I, wherein R⁶and R⁷ are independently hydrogen, fluoro, or optionally substitutedC₁-C₆ alkyl.

In some embodiments is a compound of Formula I, wherein R³ is H.

In some embodiments is a compound of Formula I, wherein R³ is R³¹. Insome embodiments is a compound of Formula I, wherein R³ is C₁-C₁₂ alkyl.In some embodiments is a compound of Formula I, wherein R³ is methyl,ethyl, propyl, butyl, or isopropyl.

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting optionally substituted C₁-C₁₂ alkenyl,optionally substituted C₁-C₁₂ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈heterocycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted alkylcycloalkyl, optionallysubstituted alkylheterocycloalkyl, optionally substituted alkylaryl, andoptionally substituted alkylheteroaryl.

In some embodiments is a compound of Formula I, wherein R³ is optionallysubstituted C₁-C₁₂ alkyl, alkyloxyalkyl, acyloxyalkyl,alkyloxycarbonyloxyalkyl, cycloalkyloxycarbonyloxyalkyl,aryloxycarbonyloxyalkyl, or alkyl-[1,3]dioxol-2-one. In some embodimentsis a compound of Formula I, wherein R³ is acyloxyalkyl. In someembodiments is a compound of Formula I, wherein R³ is —CH₂OC(═O)CH₃ or—CH₂OC(═O)C(CH₃)₃.

In some embodiments is a compound of Formula I, wherein R³ is—(R³⁰)_(q)OR³¹ or —(R³⁰)_(q)O(R³⁰)_(q)OR³¹.

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting of —R³⁰OC(O)R³¹, —R³⁰OC(O)OR³¹,—R³⁰OC(O)NHR³¹, and —R³⁰OC(O)N(R³¹)₂.

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting of:

In some embodiments is a compound of Formula I, wherein R³ is selectedfrom the group consisting of methyl, ethyl, butyl, pivaloyloxymethyl,acetoxymethyl, ethoxycarbonyloxymethyl, 1-(acetoxy)ethyl,1-(pivaloyloxy)ethyl, 1-(isopropoxycarbonyoxy)ethyl, and1-cyclohexyloxycarbonyloxymethyl.

In certain embodiments of any of the compounds of Formula I describedherein, are ring-opened compounds wherein X is

Further Forms of Compounds Disclosed Herein Isomers

In some embodiments, due to the oxophilic nature of the boron atom, thecompounds described herein may convert to or exist in equilibrium withalternate forms, particularly in milieu that contain water (aqueoussolution, plasma, etc.). Accordingly, the compounds described herein mayexist in an equilibrium between the “closed” cyclic form shown inFormula I and the “open” acyclic form shown in FIGURE Ia. In addition,the compounds described herein may associate into intramolecular dimers,trimers, and related combinations.

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein. Insome situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration, or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared as theirindividual stereoisomers by reacting a racemic mixture of the compoundwith an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomers. In some embodiments, dissociablecomplexes are preferred (e.g., crystalline diastereomeric salts). Insome embodiments, the diastereomers have distinct physical properties(e.g., melting points, boiling points, solubilities, reactivity, etc.)and are separated by taking advantage of these dissimilarities. In someembodiments, the diastereomers are separated by chiral chromatography,or preferably, by separation/resolution techniques based upondifferences in solubility. In some embodiments, the optically pureenantiomer is then recovered, along with the resolving agent, by anypractical means that would not result in racemization.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Examples of pharmaceutically acceptable salts include those saltsprepared by reaction of the compounds described herein with a mineral,organic acid or inorganic base, such salts including, acetate, acrylate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate,camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride,citrate, cyclopentanepropionate, decanoate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate,γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate,thiocyanate, tosylate undeconate and xylenesulfonate.

Further, the compounds described herein can be prepared aspharmaceutically acceptable salts formed by reacting the free base formof the compound with a pharmaceutically acceptable inorganic or organicacid, including, but not limited to, inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid metaphosphoric acid, and the like; and organic acidssuch as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citricacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid and muconic acid. In some embodiments, other acids,such as oxalic, while not in themselves pharmaceutically acceptable, areemployed in the preparation of salts useful as intermediates inobtaining the compounds of the invention and their pharmaceuticallyacceptable acid addition salts.

In some embodiments, those compounds described herein which comprise afree acid group react with a suitable base, such as the hydroxide,carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metalcation, with ammonia, or with a pharmaceutically acceptable organicprimary, secondary, tertiary, or quaternary amine. Representative saltsinclude the alkali or alkaline earth salts, like lithium, sodium,potassium, calcium, and magnesium, and aluminum salts and the like.Illustrative examples of bases include sodium hydroxide, potassiumhydroxide, choline hydroxide, sodium carbonate, N⁺(C₁₋₄ alkyl)₄, and thelike.

Representative organic amines useful for the formation of base additionsalts include ethylamine, diethylamine, ethylenediamine, ethanolamine,diethanolamine, piperazine and the like. It should be understood thatthe compounds described herein also include the quaternization of anybasic nitrogen-containing groups they contain. It should be understoodthat the compounds described herein also include the quaternization ofany boron-containing groups they contain. Such a quarternization couldresult from the treatment of the Lewis acidic boron with a Lewis base toform a complex or salt. In some embodiments, water or oil-soluble ordispersible products are obtained by such quaternization.

Pharmaceutical Compositions/Formulations

In another aspect, provided herein are pharmaceutical compositionscomprising a compound of Formula I as described herein, or apharmaceutically acceptable salt, N-oxide, or isomer thereof, and apharmaceutically acceptable excipient. In some embodiments, thepharmaceutical composition further comprises a beta-lactam antibiotic.In certain embodiments, the beta-lactam antibiotic is a penicillin,cephalosporin, carbapenem, monobactam, bridged monobactam, or acombination thereof.

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

Provided herein are pharmaceutical compositions that include a compoundof Formula I and at least one pharmaceutically acceptable inactiveingredient. In some embodiments, the compounds described herein areadministered as pharmaceutical compositions in which a compound ofFormula I is mixed with other active ingredients, as in combinationtherapy. In other embodiments, the pharmaceutical compositions includeother medicinal or pharmaceutical agents, carriers, adjuvants,preserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure, and/or buffers. Inyet other embodiments, the pharmaceutical compositions include othertherapeutically valuable substances.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula I with other chemical components (i.e.pharmaceutically acceptable inactive ingredients), such as carriers,excipients, binders, filling agents, suspending agents, flavoringagents, sweetening agents, disintegrating agents, dispersing agents,surfactants, lubricants, colorants, diluents, solubilizers, moisteningagents, plasticizers, stabilizers, penetration enhancers, wettingagents, anti-foaming agents, antioxidants, preservatives, or one or morecombinations thereof. The pharmaceutical composition facilitatesadministration of the compound to an organism. In practicing the methodsof treatment or use provided herein, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to a mammal having a disease, disorder, or condition to betreated. In some embodiments, the mammal is a human. A therapeuticallyeffective amount can vary widely depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. The compounds can be used singly or incombination with one or more therapeutic agents as components ofmixtures.

The pharmaceutical formulations described herein are administered to asubject by appropriate administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, self-emulsifying dispersions, solidsolutions, liposomal dispersions, aerosols, solid oral dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, powders,dragees, effervescent formulations, lyophilized formulations, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

Pharmaceutical compositions including a compound of Formula I aremanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compound ofFormula I as an active ingredient in free-acid or free-base form, or ina pharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use of N-oxides(if appropriate).

Pharmaceutical preparations for oral use are obtained by mixing one ormore solid excipient with one or more of the compounds described herein,optionally grinding the resulting mixture, and processing the mixture ofgranules, after adding suitable auxiliaries, if desired, to obtaintablets or dragee cores. Suitable excipients include, for example,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents are added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate. In some embodiments, dyestuffs orpigments are added to the tablets or dragee coatings for identificationor to characterize different combinations of active compound doses.

Pharmaceutical preparations that are administered orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules contain the active ingredients in admixture with filler such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive compounds are dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, stabilizers are added.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Combination Treatment

The compounds according to Formula I may be used in combination with oneor more antibiotics in the treatment of bacterial infections. Suchantibiotics may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound ofFormula I. When a compound of Formula I is used contemporaneously withone or more antibiotic, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of the present invention ispreferred. However, the combination therapy may also include therapiesin which the compound of Formula I and one or more antibiotics areadministered on different overlapping schedules. It is also contemplatedthat when used in combination with one or more antibiotics, theantibiotics may be used in lower doses than when each is used singly.

Accordingly, the pharmaceutical compositions of the present inventionalso include those that contain one or more antibiotics, in addition toa compound according to Formula I. In some embodiments, a pharmaceuticalcomposition comprising a compound of Formula I further comprises abeta-lactam antibiotic. In certain embodiments, the beta-lactamantibiotic is a penicillin, cephalosporin, carbapenem, monobactam,bridged monobactam, or a combination thereof.

The above combinations include combinations of a compound of Formula Inot only with one antibiotic, but also with two or more antibiotics.Likewise, compounds of Formula I, either in combination with anantibiotic or by themselves, may be used in combination with other drugsthat are used in the prevention, treatment, control, amelioration, orreduction of risk of bacterial infections or conditions associated withbacterial infections. Such other drugs may be administered, by a routeand in an amount commonly used therefore, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention also include those that alsocontain one or more other active ingredients, in addition to a compoundof Formula I. The weight ratio of the compound of Formula I to thesecond active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used.

In some embodiments, the compounds according to Formula I are used incombination with one or more antibiotics in the treatment of bacterialinfections. In certain embodiments, the bacterial infection is an upperor lower respiratory tract infection, a urinary tract infection, anintra-abdominal infection, or a skin infection. In some embodiments, theone or more antibiotics are selected from β-lactam antibiotics. β-Lactamantibiotics include, but are not limited to, penicillins, penems,carbapenems, cephalosporins, cephamycins, monobactams, or combinationsthereof. Penicillins include, but are not limited to, amoxicillin,ampicillin, azidocillin, azlocillin, bacampicillin, benzathinebenzylpenicillin, benzathine phenoxymethylpenicillin, benzylpenicillin(G), carbenicillin, carindacillin, clometocillin, cloxacillin,dicloxacillin, epicillin, flucloxacillin, hetacillin, mecillinam,metampicillin, meticillin, mezlocillin, nafcillin, oxacillin,penamecillin, pheneticillin, phenoxymethylpenicillin (V), piperacillin,pivampicillin, pivmecillinam, procaine benzylpenicillin, propicillin,sulbenicillin, talampicillin, temocillin, and ticarcillin. Penemsinclude, but are not limited to, faropenem. Carbapenems include, but arenot limited to, biapenem, ertapenem, doripenem, imipenem, meropenem,panipenem. Cephalosprins/Cephamycins include, but are not limited to,cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium,cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine,cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene,cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime,cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone,ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin,cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil,cefquinome, cefquinome, cefradine, cefroxadine, cefsulodin, ceftarolinefosamil, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur,ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime,cefuzonam, flomoxef, latamoxef, and loracarbef. Monobactams include, butare not limited to, aztreonam, carumonam, nocardicin A, and tigemonam.

Administration of Pharmaceutical Composition

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In some embodiments, compounds of Formula I and compositions thereof areadministered in any suitable manner. The manner of administration can bechosen based on, for example, whether local or systemic treatment isdesired, and on the area to be treated. For example, the compositionscan be administered orally, parenterally (e.g., intravenous,subcutaneous, intraperitoneal, or intramuscular injection), byinhalation, extracorporeally, topically (including transdermally,ophthalmically, vaginally, rectally, intranasally) or the like.

Parenteral administration of the composition, if used, is generallycharacterized by injection. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution of suspension in liquid prior to injection, or asemulsions. A more recently revised approach for parenteraladministration involves use of a slow release or sustained releasesystem such that a constant dosage is maintained.

Assays for Antibacterial Activity

Assays for the inhibition of beta-lactamase activity are well known inthe art. For instance, the ability of a compound to inhibitbeta-lactamase activity in a standard enzyme inhibition assay may beused (see, e g, Page, Biochem J, 295:295-304 (1993)). Beta-lactamasesfor use in such assays may be purified from bacterial sources orpreferably, are produced by recombinant DNA techniques, since genes andcDNA clones coding for many beta-lactamases are known (see, e g,Cartwright & Waley, Biochem J 221:505-12 (1984)).

Alternatively, the sensitivity of bacteria known, or engineered, toproduce a beta-lactamase to an inhibitor may be determined. Otherbacterial inhibition assays include agar disk diffusion and agardilution (see, e.g, Traub & Leonhard, Chemotherapy 43 159-67 (1997)).Thus, a beta-lactamase may be inhibited by contacting the beta-lactamaseenzyme with an effective amount of an inventive compound or bycontacting bacteria that produce the beta-lactamase enzymes with aneffective amount of such a compound so that the beta-lactamase in thebacteria is contacted with the inhibitor. The contacting may take placein vitro or in vivo. “Contacting” means that the beta-lactamase and theinhibitor are brought together so that the inhibitor can bind to thebeta-lactamase. Amounts of a compound effective to inhibit abeta-lactamase may be determined empirically, and making suchdeterminations is within the skill in the art. Inhibition includes bothreduction and elimination of beta-lactamase activity.

Methods.

The present disclosure also provides methods for inhibiting bacterialgrowth, by, e.g., reducing bacterial resistance to a β-lactamantibiotic, such methods comprising contacting a bacterial cell culture,or a bacterially infected cell culture, tissue, or organism, with abeta-lactamase inhibitor described herein. Preferably, the bacteria tobe inhibited by administration of a beta-lactamase inhibitor of FormulaI are bacteria that are resistant to beta-lactam antibiotics. The term“resistant” is well-understood by those of ordinary skill in the art(see, e g Payne et al., Antimicrobial Agents and Chemotherapy 38 767-772(1994), Hanaki et al., Antimicrobial Agents and Chemotherapy 301120-1126 (1995)).

These methods are useful for inhibiting bacterial growth in a variety ofcontexts. In certain embodiments, a compound of Formula I isadministered to an experimental cell culture in vitro to prevent thegrowth of beta-lactam resistant bacteria. In certain other embodiments,a compound of Formula I is administered to a mammal, including a humanto prevent the growth of beta-lactam resistant bacteria in vivo. Themethod according to this embodiment comprises administering atherapeutically effective amount of a beta-lactamase inhibitor for atherapeutically effective period of time to a mammal, including a human.Preferably, the beta-lactamase inhibitor is administered in the form ofa pharmaceutical composition as described above. In some embodiments, abeta-lactam antibiotic is co-administered with the beta-lactamaseinhibitor as described above.

In another aspect provided herein are methods of treating a bacterialinfection, which method comprises administering to a subject apharmaceutical composition comprising a compound of Formula I, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. In some embodiments, the methods of treating abacterial infection in a subject comprises administering to the subjecta pharmaceutical composition as described herein, optionally incombination with a beta-lactam antibiotic. In some embodiments, thebacterial infection is an upper or lower respiratory tract infection, aurinary tract infection, an intra-abdominal infection, or a skininfection.

In some embodiments, the infection that is treated or preventedcomprises a bacteria that includes Pseudomonas aeruginosa, Pseudomonasfluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes,Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia,Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii,Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi,Salmonella enteritidis, Shigella dysenteriae, Shigellaflexneri, Shigellasonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiellapneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisellatularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris,Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii,Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacterhaemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersiniapseudotuberculosis, Yersinia intermedia, Bordetella pertussis,Bordetella parapertussis, Bordetella bronchiseptica, Haemophilusinfluenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus,Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurellamultocida, Pasteurella haemolytica, Branhamella catarrhalis,Helicobacter pylori, Campylobacter fetus, Campylobacterjejuni,Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrioparahaemolyticus, Legionella pneumophila, Listeria monocytogenes,Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,Gardnerella vaginalis, Bacteroidesfragilis, Bacteroides distasonis,Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcusfaecalis,Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.

In some embodiments, the infection that is treated or preventedcomprises a bacteria that includes Pseudomonas aeruginosa, Pseudomonasfluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacterfreundii, Salmonella typhimurium, Salmonella typhi, Salmonellaparatyphi, Salmonella enteritidis, Shigella dysenteriae, Shigellaflexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes,Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens,Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersiniaenterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersiniaintermedia, Haemophilus influenzae, Haemophilus parainfluenzae,Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacterpylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli,Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis,Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, or Bacteroides splanchnicus.

Preparation of Compounds

Described herein are compounds of Formula I that inhibit the activity ofbeta-lactamases, and processes for their preparation. Also describedherein are pharmaceutically acceptable salts of such compounds.Pharmaceutical compositions comprising at least one such compound or apharmaceutically acceptable salt of such compound, and apharmaceutically acceptable excipient are also provided.

Compounds of Formula I may be synthesized using standard syntheticreactions known to those of skill in the art or using methods known inthe art. The reactions can be employed in a linear sequence to providethe compounds or they may be used to synthesize fragments which aresubsequently joined by the methods known in the art.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.),Bachem (Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000,2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd)Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). (all of which are incorporated by reference in their entirety).Other methods for the synthesis of compounds described herein may befound in U.S. Pat. No. 8,680,136; WO 01/01982901; WO 2009/064414; Arnoldet al. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170; andBurchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002)1687-1690; which are all incorporated by reference in their entirety.

The products of the reactions may be isolated and purified, if desired,using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Compounds described herein may be prepared as a single isomer or amixture of isomers.

The following compounds of Formula I are shown in Table 1 to enablethose of skill in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as illustrative and representative thereof.

TABLE 1 Examples of Compounds Example Structure MW  1

298  2

355  3

397  4

355  5

312  6

326  7

318  8

349  9

332 10

336 11

335 12

377 13

350 14

310 15

367 16

350 17

347 18

411 19

381 20

360 21

346 22

362 23

403 24

352 25

404 26

361 27

375 28

368

Example 29 Parenteral Composition of a Compound of Formula I

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a compound of Formula I, or awater soluble pharmaceutically acceptable salt thereof, is dissolved inDMSO and then mixed with 10 ml of 0.9% sterile saline solution. Themixture is incorporated into a dosage unit suitable for administrationby injection.

Example 30 Oral Composition of a Compound of Formula I

To prepare a pharmaceutical composition for oral delivery, 400 mg of acompound of Formula I and the following ingredients are mixed intimatelyand pressed into single scored tablets.

Tablet Formulation

Ingredient Quantity per tablet mg compound 400 cornstarch 50croscarmellose sodium 25 lactose 120 magnesium stearate 5

The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule.

Capsule Formulation

Ingredient Quantity per capsule mg compound 200 lactose spray dried 148magnesium stearate 2

Biological Examples Example I Experimental Method for R-Lactamase EnzymeAssays Isolation of β-Lactamases.

For SHV-5, Kpc-2, p99AmpC and OXA-1 β-lactamases, E. coli BL21(DE3)bacterial cells carrying expression plasmids (expressed as nativeuntagged proteins) for the individual β-lactamases were grown in 1 L ofSuperbroth (Teknova Inc. Hollister, Calif.) supplemented with 100 μg/mlkanamycin selection and 1×5052 (0.5% glycerol, 0.05% glucose and 0.2%α-lactose) at 35° C. for 18-20 hours. Cells were harvested bycentrifugation (4,000×g, 4° C., 20 min), resuspended in 50 ml of 10 mMHEPES pH 7.5 ( 1/20 of the initial volume). The cells were lysed bysonication (5 pulses of 45 seconds) at 45 W on ice. The lysates wereclarified by centrifugation at 10,000×g for 40 minutes at 4° C. Sampleswere diluted 5-fold in 50 mM sodium acetate pH 5.0, stored overnight at4° C., after which they were centrifuged at 10,000×g for 30 minutes toclarify, and filtered through 0.45 μm filters. The samples were loadedonto a 5 ml Capto S sepharose cation exchange column (GE Healthcare)pre-equilibrated with 50 mM sodium acetate pH 5.0. The column was washedwith 5 column volumes of 50 mM sodium acetate pH 5.0 to wash out unboundprotein and a linear gradient of NaCl (0 to 500 mM) was used to elutethe protein (over 16 CV) from the column. Fractions were assayed forβ-lactamase activity using Centa (Calbiochem, Gibbstown, N.J.) orNitrocefin (EMD Millipore chemicals, Darmstadt, Germany) as a reporterβ-lactamase substrate for activity in the isolated fractions. Activefractions were pooled, concentrated and further purified by gelfiltration chromatography on a Superdex 75 prep grade gel filtrationcolumn (GE Healthcare, Piscataway, N.J.) pre-equilibrated in 50 mM HepespH 7.5, 150 mM NaCl. Active fractions were pooled concentrated,quantitated by BCA protein determination (Thermo Scientific, Rockford,Ill.), dialyzed into PBS and frozen at −80° C. in 20% glycerol untiluse.

For Vim-2 metallo β-lactamase, the procedure was identical with thefollowing exceptions, first the protein was not pH adjusted to pH 5 with50 mM sodium acetate, second, the chromatography step was changed to a 5ml Q sepharose anion exchange column pre-equilibrated with 50 mM HepespH 7.5, and elution of the protein was achieved by a linear gradient ofNaCl (0-600 mM). Finally, the VIM-2 purification required a second run(3^(rd) step) on the Q sepharose anion exchange column to achieveacceptable purity (>90%).

β-Lactamase Inhibition.

To determine the level of inhibition of β-lactamase enzymes, compoundsare diluted in PBS at pH 7.4 to yield concentrations ranging from 100 to0.00005 μM in 96-well microtiter plates. An equal volume of dilutedenzyme stock is added, and the plates are incubated at 37° C. for 15min. Nitrocefin is used as substrate for p99 AmpC, VIM-2 and OXA-1 anddispensed into each well at a final concentration of 100 μM. Absorbanceat 486 nm is immediately monitored for 10 min using a Biotek PowerwaveXS2 microplate spectrophotometer using the GEN5 softweare package(Biotek Instruments, Winooski Vt.). In an analogous fashion, imipenem isused as substrate for Kpc-2 and Cefotaxime is used for SHV-5, whilechanges in absorbance upon hydrolysis of the β-lactam ring are monitoredat 300 nm and 260 nm respectively in UV-transparent 96-well microtiterassay plates. Maximum rates of hydrolysis are compared to those incontrol wells (without inhibitors), and percentages of enzyme inhibitionare calculated for each concentration of inhibitor. The concentration ofinhibitor needed to reduce the initial rate of hydrolysis of substrateby 50% (IC₅₀) is calculated as the residual activity of β-lactamase at486 nm using GraFit version 7 kinetics software package (ErithacusSoftware, Surrey, UK).

Example II In Vitro Antibacterial Assays of R-Lactamase Inhibition

To determine the ability of test compounds to potentiate the inhibitionof the growth of bacterial strains that produce beta-lactamase enzymes,classic cell based broth microdilution MIC assays are employed. Sixbacteria strains producing beta-lactamase enzymes are used: E. coliexpressing the Class A Extended Spectrum Beta-Lactamase (ESBL) CTX-M-15,E. cloacae expressing the Class C P99, K. pneumoniae expressing theClass A carbapenemase KPC-3, P. aeruginosa expressing the Class Bcarbapenemase VIM-2, K. pneumoniae expressing the class A carbapenemaseKPC-2 and the class B carbapenemase VIM-4, and S. aureus producing theClass A penicillinase PC-1. The assay is conducted in Cation AdjustedMueller Hinton Broth (CAMHB, BD #212322, BD Diagnostic Systems, Sparks,Md.). Bacteria strains are grown for 3-5 hours in CAMBH broth. Testcompounds are added to a microtiter plate in 2-fold serial dilutions inCAMHB in a final concentration range of 32 μg/mL to 0.25 μg/ml. Anoverlay of CAMHB containing a Beta-lactam is added to the compounds at afinal static concentration of 4 μg/mL. Ceftazidime (CAZ, Sigma#C3809-1G, Sigma-Aldrich, St. Louis, Mo.) is used as the partnerantibiotic for E. coli expressing Ambler Class A ESBL CTX-M-15 (MICalone >128 μg/ml), and E. cloacae expressing Class C P99 (MIC alone=128μg/mL). Meropenem (Mero, USP #1392454, U.S. Pharmacopeia, Rockville,Md.) is used as the partner antibiotic for K. pneumoniae expressingAmbler Class A carbapenemase KPC-3 (MIC alone >128 μg/mL), P. aeruginosaexpressing Class A carbapenemase VIM-2 (MIC alone=16 μg/mL), and K.pneumoniae expressing the Ambler Class A carbapenemase KPC-2 and AmblerClass B carbapenemase VIM-4 (MIC alone=64 μg/mL). Piperacillin (Pip,Fisher #ICN15626801, MP Biomidicals, Solon, Ohio) is used as the partnerantibiotic for S. aureus producing the Class A penicillinase PC-1 (MICalone=64 μg/ml). Titration of test compounds with MIC readout indicatesthe concentration of test article needed to sufficiently inhibitbeta-lactamase enzyme activity and protect the intrinsic antibacterialactivity of the beta-lactam. In addition to the titration of testcompounds, the MICs of a panel of control beta-lactams is also tested toensure the strains are behaving consistently from test to test. Once thetest compound and antibiotics are added the plates can be inoculatedaccording to CLSI broth microdilution method. After inoculation theplates are incubated for 16-20 hours at 37° C. then the MinimalInhibitory Concentration (MIC) of the test compound is determinedvisually.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1. A compound of Formula (I) or a pharmaceutically acceptable salt,N-oxide, or isomer thereof:

wherein: L is a bond, —C(R¹R²)—, —C(═O)—, or ═C(R¹)—; M is a bond, —O—,—S—, —S(O)—, —S(O)₂—, or —N(R⁴)—; m is 0, 1, or 2; n is 0, 1, 2, or 3; pis 0, 1, 2, 3, or 4; Z is —C(═O)—, —C(═S), or —S(O)₂—; A is CycA, ArA orHetA, wherein CycA is an optionally substituted 3-10 memberednon-aromatic carbocycle, wherein an optional olefin functionality of thenon-aromatic carbocycle is not directly attached to an oxygen, sulfur,or nitrogen substituent; ArA is an aromatic or heteroaromatic ringsystem optionally substituted with one or more substituents selectedfrom the group consisting of fluoro, chloro, bromo, —CN, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₆ cycloalkyl,optionally substituted heterocycle, optionally substituted aryl,optionally substituted heteroaryl, —OH, —OR¹⁰, and —SR¹⁰; HetA is anoptionally substituted non-aromatic heterocyclic ring system; each R¹and R² is independently selected from the group consisting of hydrogen,fluoro, chloro, bromo, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, and —NR⁴R⁵, or R¹ andR² taken together form an oxo, oxime, or an optionally substitutedcarbocycle or optionally substituted heterocycle with the carbon towhich they are attached; each R^(d), R⁴, and R⁵ is independentlyselected from the group consisting of hydrogen, —OH, —CN, optionallysubstituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl, optionallysubstituted hydroxyalkyl, optionally substituted aminoalkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclylalkyl,optionally substituted aralkyl, optionally substituted heteroaralkyl,(poly-ethylene-glycol)-ethyl, and an optionally substituted saccharide;or R⁴ and R⁵ taken together form an optionally substituted heterocyclewith the nitrogen to which they are attached; each R¹⁰ is independentlyselected from the group consisting of optionally substituted C₁-C₆ alkyland optionally substituted C₃-C₆ cycloalkyl; each Y is independently agroup comprising 1-50 non-hydrogen atoms selected from the groupconsisting of C, N, O, S, and P; and X is

J is a 1-4 atom alkylene or 1-4 atom alkenylene, optionally substitutedby one or more substituents selected from the group consisting of Cl, F,CN, CF₃, —R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, and —C(═O)OR¹⁹, wherein said 1-4atom alkylene or 1-4 atom alkenylene is optionally fused to anoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted carbocyclyl, or optionally substitutedheterocyclyl; R³ is selected from the group consisting of R³¹,—(R³⁰)_(q)OR³¹, —(R³⁰)_(q)O(R³⁰)_(q)OR³¹, —R³⁰OC(O)R³¹, —R³⁰OC(O)OR³¹,—R³⁰OC(O)NHR³¹, —R³⁰OC(O)N(R³¹)₂, optionally substituted alkyloxyalkyl,optionally substituted acyloxyalkyl, optionally substitutedalkyloxycarbonyloxyalkyl, optionally substitutedcycloalkyloxycarbonyloxyalkyl, optionally substitutedaryloxycarbonyloxyalkyl, and optionally substitutedalkyl-[1,3]dioxol-2-one; each R³⁰ is independently —CH₂—, —CH(CH₃)—,—C(CH₃)₂—, or optionally substituted 1,1′-cyclopropylene; R³¹ isselected from the group consisting of optionally substituted C₁-C₁₂alkyl, optionally substituted C₁-C₁₂ alkenyl, optionally substitutedC₁-C₁₂ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ heterocycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted alkylcycloalkyl, optionally substitutedalkylheterocycloalkyl, optionally substituted alkylaryl, and optionallysubstituted alkylheteroaryl; each q is independently 2, 3, 4, 5, or 6;R¹⁶ is selected from a group consisting of H, —C₁-C₉alkyl,—C₂-C₉alkenyl, —C₂-C₉alkynyl, carbocyclyl, —C₁-C₉alkylR²¹,—C₂-C₉alkenylR²¹, —C₂-C₉alkynylR²¹, carbocyclylR²¹, —C(═O)OR¹⁹,—C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹, —C₂-C₉alkynylC(═O)OR¹⁹,carbocyclylC(═O)OR¹⁹, or alternatively: (i) R¹⁶ and an R¹⁷ are takentogether with the atoms to which they are attached to form a substitutedor unsubstituted carbocyclyl or substituted or unsubstitutedheterocyclyl, (ii) R¹⁶ and a carbon atom in J are taken together withintervening atoms to form a substituted or unsubstituted carbocyclyl orsubstituted or unsubstituted heterocyclyl, or (iii) R¹⁶ is absent whenthe carbon to which it is attached is a ring atom in an aryl orheteroaryl ring; each R¹⁷ is independently selected from a groupconsisting of H, halo, —C₁-C₉alkyl, —C₂-C₉alkenyl, —C₂-C₉alkynyl,NR¹⁹R²⁰, —OR¹⁹, —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,—C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or independently: (i) R¹⁶and an R¹⁷ are taken together with the atoms to which they are attachedto form a substituted or unsubstituted carbocyclyl or substituted orunsubstituted heterocyclyl, (ii) R¹⁷ and an R¹⁸ are taken together withthe atoms to which they are attached to form a substituted orunsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl,(iii) an R¹⁷ and a carbon atom in J are taken together with interveningatoms to form a substituted or unsubstituted carbocyclyl or substitutedor unsubstituted heterocyclyl; each R¹⁸ is independently selected from agroup consisting of H, halo, —C₂-C₉alkenyl, —C₂-C₉alkynyl, NR¹⁹R²⁰,—OR¹⁹, —C₁-C₉alkylC(═O)OR¹⁹, —C₂-C₉alkenylC(═O)OR¹⁹,—C₂-C₉alkynylC(═O)OR¹⁹, carbocyclylC(═O)OR¹⁹, or independently: (i) anR¹⁷ and an R¹⁸ are taken together with the atoms to which they areattached to form a substituted or unsubstituted carbocyclyl orsubstituted or unsubstituted heterocyclyl, (ii) a geminal R¹⁷ and R¹⁸together form —C₂-C₉alkenylC(═O)OR¹⁹, or (iii) each R¹⁸ attached to aring atom forming part of a substituted or unsubstituted aryl is absent;each R¹⁹ is independently selected from a group consisting of H,—C₁-C₉alkyl, —C₂-C₉alkenyl, —C₂-C₉alkynyl, carbocyclyl, —C₁-C₉alkylR²¹,—C₂-C₉alkenylR²¹, —C₂-C₉alkynylR²¹, carbocyclylR²¹, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, and substituted or unsubstitutedheterocyclyl; each R²⁰ is independently selected from a group consistingof H, —C₁-C₉alkyl, —OR¹⁹, —CH(═NH), —C(═O)OR¹⁹, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted carbocyclyl, and substituted or unsubstitutedheterocyclyl; each R²¹ is independently selected from a group consistingof substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted carbocyclyl, and substituted orunsubstituted heterocyclyl; and r is 0 or 1, wherein each —C₁-C₉alkyl,—C₂-C₉alkenyl, and —C₂-C₉alkynyl is independently optionallysubstituted.
 2. The compound of claim 1, wherein: X is

 and R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃, —R¹⁹,—OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹; or X is

 and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹; or X is

 and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹; or X is

 and R²² and R²⁴ are independently H, Cl, F, CN, CF₃, —R¹⁹, —OR¹⁹,—C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹; or X is

 and each R²², R²³, and R²⁴ are independently H, Cl, F, CN, CF₃, —R¹⁹,—OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹; or X is

 and each R²², R²³, R²⁴, and R²⁵ are independently H, Cl, F, CN, CF₃,—R¹⁹, —OR¹⁹, —C(═O)NR¹⁹R²⁰, or —C(═O)OR¹⁹. 3.-23. (canceled)
 24. Thecompound of claim 1, wherein R¹⁶, R¹⁷, and R¹⁸ are H; R^(d) is hydrogen;and Z is —C(═O)—. 25.-27. (canceled)
 28. The compound of claim 1,wherein n is 0; or n is 1, and R¹ and R² are hydrogen.
 29. (canceled)30. The compound of claim 1, wherein M is a bond; m is 0; and L is abond. 31.-32. (canceled)
 33. The compound of claim 1, wherein A is HetA;and HetA is selected from the group consisting of piperidine,piperazine, pyrrolidine, tetrahydropyran, and tetrahydrofuran. 34.-35.(canceled)
 36. The compound of claim 1, wherein A is cyclohexyl, phenyl,or pyridyl. 37.-40. (canceled)
 41. The compound of claim 1, wherein eachY, provided Y is not attached directly to a heteroatom of HetA, isselected from the group consisting of: fluoro, chloro, bromo, —CN,optionally substituted C₁-C₆ alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocycle, optionally substitutedaryl, optionally substituted heteroaryl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵,—(CR⁶R⁷)_(v)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —O(CR⁶R⁷)_(v)NR⁴R⁵,—S(O)_(0,1,2)(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(v)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)OR¹⁰, —NR⁴(CR⁶R⁷)_(v)S(O)_(0,1,2)R¹⁰,—C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —S(O)_(0,1,2)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —OC(O)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵,—NR⁵C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶,—(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁵)N⁴R⁵, —S(O)_(0,1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—O(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—S(O)_(0,1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—O(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—S(O)_(0,1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —NR⁴C(═NR⁵)NR⁴R⁵,—C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴C(O)R⁶, —NR⁴SO₂R⁶, —NR⁴C(O)R⁶, —NR⁴C(═O)OR⁶,—C(O)NR⁴R⁵, —(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵, -Heteroaryl-NR⁴R⁵,-Heterocyclyl-NR⁴R⁵, -Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,-Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —N(R⁴)—Heteroaryl-NR⁴R⁵,—N(R⁴)—Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl,—(CR⁶R⁷)_(v)Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl,—NR⁴(CR⁶R⁷)_(v)Heteroaryl, —NR⁴(CR⁶R⁷)_(v)Heterocyclyl,—O(CR⁶R⁷)_(v)Heteroaryl, —O(CR⁶R⁷)_(v)Heterocyclyl,—NR⁴(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —NR⁴(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,—O(CR⁶R⁷)_(v)NR⁵-Heteroaryl, —O(CR⁶R⁷)_(v)NR⁵-Heterocyclyl,—O(CR⁶R⁷)_(v)O-Heterocyclyl, —NR⁴R⁵R⁹⁺Q⁻, —(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻,—NR⁴(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻, —NR⁴R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂,—(CR⁶R⁷)_(v)(T)⁺Q⁻, and —O(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻; wherein: T ispyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl; Q is a pharmaceuticallyacceptable counterion; each R⁶ and R⁷ are independently selected fromthe group consisting of hydrogen, fluoro, chloro, bromo, optionallysubstituted C₁-C₆ alkyl, optionally substituted alkoxyalkyl, optionallysubstituted hydroxyalkyl, optionally substituted C₃-C₆ cycloalkyl, —OH,—OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵, —C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl; or R⁶ and R⁷ taken together form an oxo, oxime,or an optionally substituted carbocycle or an optionally substitutedheterocycle with the carbon to which they are attached; R⁹ is optionallysubstituted C₁-C₆ alkyl; and v is 1-4; or two Ys taken together with thecarbon atoms to which they are attached form an optionally substitutedcarbocycle, an optionally substituted heterocycle, or a carbonyl group;or in the case where Y is attached directly to a heteroatom of HetA, Yis selected from the group consisting of: —(CR⁶R⁷)_(v)NR⁴R⁵,—S(O)_(1,2)(CR⁶R⁷)_(v)NR⁴R⁵, —C(O)(CR⁶R⁷)_(v)NR⁴R⁵,—(CR⁶R⁷)_(w)N(R⁴)C(O)(CR⁶R⁷)_(v)NR⁴R⁵, —(CR⁶R⁷)_(w)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵,—NR⁴(CR⁶R⁷)_(w)OR¹⁰, —(CR⁶R⁷)_(w)S(O)_(0,1,2)R¹⁰,—C(O)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵, —S(O)_(1,2)NR⁴(CR⁶R⁷)_(w)NR⁴R⁵,—C(═NR⁷)NR⁴(CR⁶R⁷)_(v)NR⁴R⁵, —C(═NR⁵)R⁶, —(CR⁶R⁷)_(w)N(R⁴)C(═NR⁵)R⁶,—S(O)_(1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)R⁶, —(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(w)C(═NR⁵)NR⁴R⁵, —S(O)_(1,2)(CR⁶R⁷)_(v)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)_(w)N(R⁴)C(═NR⁵)NR⁴R⁵, —S(O)_(1,2)(CR⁶R⁷)_(v)N(R⁴)C(═NR⁵)NR⁴R⁵,—C(═NR⁵)NR⁴C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵,—S(O)_(1,2)—(CR⁶R⁷)_(v)C(═NR⁴)NR⁵C(═NR⁴)NR⁴R⁵, —C(═NR⁴)NR⁴R⁵,—C(═NR⁴)NR⁴C(O)R⁶, —SO₂R⁶, —C(O)R⁶, —C(═O)OR⁶, —C(O)NR⁴R⁵,—(CR⁶R⁷)_(v)C(O)NR⁴R⁵, —SO₂NR⁴R⁵, -aryl, -heteroaryl,—C(O)N(R⁴)—Heteroaryl-NR⁴R⁵, -Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵,-Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵, -Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵,-Heteroaryl-NR⁴R⁵, -Heterocyclyl-NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl-NR⁴R⁵,—(CR⁶R⁷)_(v)Heterocyclyl-NR⁴R⁵,—(CR⁶R⁷)^(v)Heteroaryl-N(R⁴)C(═NR⁵)NR⁴R⁵,—(CR⁶R⁷)^(v)Heterocyclyl-N(R⁴)C(═NR⁵)NR⁴R⁵, —(CR⁶R⁷)_(v)Heteroaryl,—(CR⁶R⁷)_(v)Heterocyclyl, —(CR⁶R⁷)_(v)NR⁵-Heteroaryl,—(CR⁶R⁷)_(v)NR⁵-Heterocyclyl, —(CR⁶R⁷)_(v)O-Heterocyclyl, —R⁹⁺Q⁻,—(CR⁶R⁷)_(w)NR⁴R⁵R⁹⁺Q⁻, —R⁹⁺(CR⁶R⁷)_(v)NR⁴R⁵R⁹⁺Q⁻ ₂ and—(CR⁶R⁷)_(v)(T)⁺Q; wherein: T is pyridin-1-yl, pyrimidin-1-yl, orthiazol-3-yl; Q is a pharmaceutically acceptable counterion; each R⁶ andR⁷ are independently selected from the group consisting of hydrogen,fluoro, chloro, bromo, optionally substituted C₁-C₆ alkyl, optionallysubstituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionallysubstituted C₃-C₆ cycloalkyl, —OH, —OR¹⁰, —SR¹⁰, —NR⁴R⁵, —NR⁴C(O)R⁵,—C(O)NR⁴R⁵, —NR⁴SO₂R⁵, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl; or R⁶ and R⁷taken together form an oxo, oxime, or an optionally substitutedcarbocycle or an optionally substituted heterocycle with the carbon towhich they are attached; R⁹ is optionally substituted C₁-C₆ alkyl; v is1-4; and w is 2-4. 42.-45. (canceled)
 46. The compound of claim 41,wherein at least one Y is 2-(NR⁴R⁵)-pyridyl, 2-(NR⁴R⁵)-pyrimidinyl,2-(NR⁴R⁵)-thiazolyl, 2-(NR⁴R⁵)-imidazolyl, 3-(NR⁴R⁵)-pyrazolyl,3-(NR⁴R⁵)-isothiazolyl, 2-(NR⁴R⁵)-oxazolyl, piperidine, pyrrolidine,4-amino-piperidinyl, 3-amino-pyrrolidinyl, piperazine, or4-carboximidoyl-piperazinyl.
 47. The compound of claim 1, wherein two Ygroups, together with the atoms to which they are attached form apyrrolidine ring.
 48. The compound of claim 1, wherein p is 1 or
 2. 49.The compound of claim 1, wherein R⁴ and R⁵ are independently selectedfrom the group consisting of hydrogen, optionally substituted C₁-C₆alkyl, optionally substituted alkoxyalkyl, optionally substitutedhydroxyalkyl, and optionally substituted heterocyclyl. 50.-52.(canceled)
 53. The compound of claim 1, wherein R³ is H; optionallysubstituted C₁-C₁₂ alkyl, alkyloxyalkyl, acyloxyalkyl,alkyloxycarbonyloxyalkyl, cycloalkyloxycarbonyloxyalkyl,aryloxycarbonyloxyalkyl, or alkyl-[1,3]dioxol-2-one. 54.-61. (canceled)62. The compound of claim 1, wherein R³ is selected from the groupconsisting of —R³⁰OC(O)R³¹, —R³⁰OC(O)OR³¹, —R³⁰OC(O)NHR³¹, and—R³⁰OC(O)N(R³¹)₂.
 63. The compound of claim 1, wherein R³ is selectedfrom the group consisting of:


64. (canceled)
 65. The compound of claim 1, wherein the compound isselected from the group represented by the following structures:

or a pharmaceutically acceptable salt, N-oxide, or isomer thereof.
 66. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, N-oxide, or isomer thereof; and apharmaceutically acceptable excipient.
 67. The pharmaceuticalcomposition of claim 66, further comprising a beta-lactam antibiotic.68. The pharmaceutical composition of claim 67, wherein the beta-lactamantibiotic is a penicillin, cephalosporin, carbapenem, monobactam,bridged monobactam, or a combination thereof.
 69. A method of treating abacterial infection in a subject, comprising administering to thesubject a pharmaceutical composition of claim 66, optionally incombination with a beta-lactam antibiotic.